Doxycycline, an anti-inflammatory agent, alleviates dyskinesia induced by L-DOPA in Parkinsonian rats

Abstract

Background and Purpose L-DOPA induced dyskinesia is a debilitating side effect of treating Parkinson's disease with L-DOPA. There is a need to discover a treatment that has the same benefits as L-DOPA treatment without the associated side effects. Here, we demonstrate the anti-dyskinetic potential of doxycycline and the analog compound COL-3 (without antimicrobial activity) in hemiparkinsonian rats presenting L-DOPA-induced dyskinesia. Experimental Approach Wistar adult male rats received a unilateral medial forebrain bundle injection of 6-hydroxydopamine and were then orally administered L-DOPA once a day for 14 days. This resulted in dyskinetic-like behavior. Key Results A single injection of doxycycline (intraperitoneal) or COL-3 (intracerebroventricular) together with L-DOPA attenuated the dyskinesia. Co-treatment with doxycycline from the first day of L-DOPA suppressed the onset of dyskinesia. The improved motor responses to L-DOPA remained intact in the presence of doxycycline or COL-3, indicating the preservation of the L-DOPA benefits. Doxycycline treatment was associated with decreased expression of FosB, cyclooxygenase-2, astrocytes, and microglia, which had previously been found to be elevated in the basal ganglia of rats exhibiting dyskinesia. In addition, metalloproteinase-2/-9 activity, metalloproteinase-3 expression, and production of reactive oxygen species in the basal ganglia of dyskinetic rats showed a significant positive correlation with the intensity of dyskinesia, which was decreased with the doxycycline treatment. Conclusion and Implications Given the longestablished and safe use of doxycycline and the similar effect of COL-3 (without antimicrobial activity), this study indicates that both drugs should undergo testing for their ability to reduce signs of dyskinesia induced by L-DOPA in patients with Parkinson's disease. Bullet point summary:'What is already known', Repeated treatment with L-DOPA induces dyskinesia (LID) in patients with Parkinson's disease (PD). Doxycycline is a clinically used antibiotic that posses dopamine neuroprotective properties and antiinflammatory activity.

Neuron glial antigen 2 in the striatum of parkinsonian rats presenting L-DOPA induced dyskinesia

“…Therefore, a potential doxycycline interference on L-DOPA gastrointestinal absorption cannot be ruled out. However, this is an unlikely possibility because previous research from our group (Bortolanza et al, 2020) provide evidences of no drug interference with the positive motor effects of L-DOPA and the anti-dyskinetic effects of doxycycline were still present when L-DOPA was administered subcutaneously. The large majority of NG2-glia in the adult brain is maintained in a quiescent state under physiological conditions (Hughes et al, 2013).…”

“…We examined NG2-glia distribution in the lesioned striatum, the cells' phenotypic characteristics, and the association with astrocytes and microglia cells. Because molecules capable of modulating glial cells' activation were effective in resolving LID, we determine the antidyskinetic effect of doxycycline (6-Deoxy-5-hydroxytetracycline, Bortolanza et al, 2020), in NG2 expression and NG2-glia activation.…”

Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

“…In particular, drugs with well-characterized anti-inflammatory activity, as the glucocorticoid corticosterone and the non-selective COX inhibitor ibuprofen have proved capable of largely attenuate dyskinesia ( Teema et al, 2016 ). Similarly, two tetracycline derivatives doxycycline and COL-3 that possess anti-inflammatory properties, efficiently inhibited dyskinesia in L-DOPA-treated parkinsonian rats ( Bortolanza et al, 2020 ). We also found that co-administration of the TRPV-1 ion channel antagonist capsazepine (CPZ) with cannabidiol (CBD), a cannabis derivative with well-reported anti-inflammatory properties ( Napimoga et al, 2009 ; Campos et al, 2012 ; Mori et al, 2017 ; Sonego et al, 2018 ; Dos-Santos-Pereira et al, 2020 ) improves abnormal involuntary movements induced by L-DOPA in a hemiparkinsonian dyskinetic mouse model ( Dos-Santos-Pereira et al, 2016 ; Junior et al, 2020 ).…”